The chematherapeutic management of advanced breast cancer is suboptimal, and results have plateaued in recent years. Investigation of new treatment approaches is warranted. In this proposal we plan to examine one such approach by utilizing the potential endocrine dependence of human breast cancer in a fashion designed to increase the cytotoxic effects of certain drugs. Experimental evidence suggests that tumor cell kinetics may be important in determining the resistance or sensitivity of the tumor to the chemotherapy. Hormone manipulation may be a direct method of favorably altering the kinetics of a breast cancer prior to administration of drug. First we plan to determine the effects of insulin, antiestrogens and estrogens on the cell cycle kinetics of hormone-responsive human breast cancer cells growing in vitro in tissue culture and in vivo in nude mice. The proliferative fraction as well as cell cycle phase durations will be estimated by autoradiographic and flow microfluorometric techniques. Then, we will determine whether the sensitivity of the cells to cytotoxic drugs can be enhanced by hormonal manipulation of these cell cycle parameters. These studies may provide a rational basis for new treatment strategies in patients with this disease.